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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 119-131

The current approaches to the management of coronavirus disease 2019 associated coagulopathy


1 Department of General Surgery and Radiology, Pirogov Russian National Research Medical University, Moscow, Russian Federation
2 The First Phlebological Center, Moscow, Russian Federation
3 Department of Cardiovascular Surgery, Mechnikov's North-Western State Medical University, Saint Petersburg, Russian Federation

Date of Submission09-Jun-2020
Date of Decision15-Jun-2020
Date of Acceptance17-Jun-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Dr. Kirill Lobastov
10 Pistsovaya Str., Moscow Clinical Hospital No 24, Department of General Surgery and Radiology, Moscow, 127015
Russian Federation
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/VIT.VIT_19_20

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  Abstract 


Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by the severe acute respiratory syndrome-CoV-2 virus that appeared in China and has spread globally. Accumulating evidence suggests that the development of specific prothrombotic changes in patients with COVID-19 reflected a high incidence of thrombotic complications. This paper is a narrative review of the diagnostic and management of COVID-19-associated coagulopathy and related venous thromboembolism (VTE). The consecutive search and review of relevant literature were carried out between March 23 and May 22, 2020. Eleven studies assessing the incidence of VTE and eleven guidelines on the management of coagulopathy were identified. The prevalence of VTE in patients with COVID-19 appeared to be unexpectedly high, reaching 8%–13% in the general ward and 9%–18% in the intensive care unit despite pharmacological prophylaxis. The current guidelines suggest prophylactic anticoagulation with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in all inpatients. Intensified anticoagulation in the absence of VTE is not generally recommended but may be considered for patients with obesity, elevated D-dimer, an individually highest risk of VTE, or critical illness. The value of mechanical prophylaxis is underestimated. Extended prophylaxis after discharge may be indicated for patients with increased risk of VTE and low risk of bleeding. Increased D-dimer may be used as an indication for VTE screening by appropriate imaging tests. If VTE is highly suspected according to the clinical signs or D-dimer, then therapeutic anticoagulation may be initiated before VTE confirmation. For putative or confirmed VTE, therapeutic anticoagulation with LMWH or UFH is preferred during inpatient treatment, followed by switching to direct oral anticoagulants after discharge for 3 months. Primary VTE prophylaxis for outpatients is not generally recommended. Most of the guidelines are interim and ambiguous.

Keywords: Anticoagulants, coronavirus disease 2019, prophylaxis, treatment, venous thromboembolism


How to cite this article:
Lobastov K, Schastlivtsev I, Porembskaya O, Dzhenina O, Bargandzhiya A, Tsaplin S. The current approaches to the management of coronavirus disease 2019 associated coagulopathy. Vasc Invest Ther 2020;3:119-31

How to cite this URL:
Lobastov K, Schastlivtsev I, Porembskaya O, Dzhenina O, Bargandzhiya A, Tsaplin S. The current approaches to the management of coronavirus disease 2019 associated coagulopathy. Vasc Invest Ther [serial online] 2020 [cited 2021 Jan 27];3:119-31. Available from: https://www.vitonline.org/text.asp?2020/3/4/119/304836




  Introduction Top


Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by the severe acute respiratory syndrome (SARS)-CoV-2 virus that appeared in Wuhan, Hubei Province, China, and that has spread globally.[1] According to data from the World Health Organization, as of June 6, 2020, the total number of infected persons was >6.5 million, with >380,000 deceased.[2] Thus, the mortality rate is estimated to be 5.9%. Furthermore, COVID-19 has turned out to be demanding on medical resources. Of all infected persons with a clinical presentation, about 20% require hospital admission, 2%–26% require access to the intensive care unit (ICU), 1%–30% require mechanical ventilation, and 3% require kidney replacement therapy.[1],[3],[4],[5] COVID-19 infection leads to severe respiratory illness similar to that caused by SARS coronavirus that results in interstitial pneumonia and acute respiratory distress syndrome (ARDS) that requires noninvasive and invasive ventilation. The mortality of those who receive mechanical ventilation reaches 88%.[3] The other feature of COVID-19 is a pronounced prothrombotic status and a high number of thrombotic events, especially venous thromboembolic events (VTE), which were observed in the first reports from China.[6],[7] Later, this clinical feature was called “COVID-19 coagulopathy.”[8] The underlying mechanisms of, and therapeutic approaches for, this pathology are currently under debate. Due to the evidence, the current guidelines represent high inconsistency in recommendations and solutions.

Thereby, we conducted a review of all identified guidelines form the professional societies and health-care providers as well as related literature found in PubMed and Medline. The search was performed consistently between March 23 and May 22, with the final update on May 23. It was limited to the English language.


  Evidence of Coronavirus Disease 2019 Coagulopathy Top


There is increasing evidence of prothrombotic changes, predominantly in patients with severe forms of infection admitted to the hospital. The central laboratory abnormalities are represented by an increased level of D-dimer, prolonged prothrombin time (PT), decreased level of platelets, and changes in fibrinogen level. The level of D-dimer at admission was assessed in eight studies and appeared to be significantly higher in: patients with severe disease as compared to patients with nonsevere disease; patients admitted to ICU as compared to patients not admitted to ICU; and nonsurvivors as compared to survivors.[4],[5],[9],[10],[11],[12],[13],[14] Zhou et al. found that the D-dimer level of >1.0 mg/L increased the risk of death by 18.4 times (95% confidence interval [CI] of 2.6–129.6).[12] The correlation between D-dimer level and mortality rate in patients with suspected noncoronavirus infection and sepsis has been reported previously.[15]

The PT was assessed in nine studies. No significant prolongation was observed in severe disease compared to nonsevere disease.[9],[10] In ICU patients, as compared to non-ICU patients, PT was prolonged in general, but not always significantly.[4],[11] When nonsurvivors were compared to survivors, three studies showed a significant prolongation, one study showed a nonsignificant prolongation, and the last study showed a shortening of PT is deceased patients.[5],[12],[14],[16],[17]

The same inconsistency was found in five studies comparing the level of platelets in ICU and non-ICU patients or nonsurvivors and survivors.[4],[11],[12],[16],[17] However, the further meta-analysis of nine studies combining 1799 patients demonstrated a significant correlation between platelet level and outcome.[18] Severe infection, as compared to nonsevere infection, was associated with a platelet drop of 31 (95% CI, 29–35) × 109/L, while in lethal disease, as compared to nonlethal disease, there was a platelet decline of 48 (95% CI, 39–57) × 109/L. In total, the decrease in platelet level below the individual threshold determined by the study increased the risk of severe disease by 5.1 times (95% CI, 1.8–14.6). This inconsistency in platelet level may be explained by different mechanisms of their consumption described as disseminated intravascular coagulation (DIC), thrombotic microangiopathy (TMA), and heparin-induced thrombocytopenia (HIT), in parallel with their increase as a response to acute infection.[14],[19],[20]

Five studies measured the level of fibrinogen at admission to the hospital. Two of them found no difference in patients with severe disease as compared to patients with nonsevere infection and in survivors as compared to nonsurvivors.[9],[14] On the other hand, the remaining studies showed a significant increase in fibrinogen level in severe illness as compared to nonsevere illness; in nonsurvivors as compared to survivors; in COVID-19 patients with ARDS as compared to those without ARDS and to a noncoronavirus acute respiratory infection; and in ICU patients with ARDS due to novel disease as compared to a historical group of noncoronavirus ARDS.[10],[21],[22],[23]

The coagulation abnormalities may be identified not only at admission. Two studies assessed their changes over time. Tang et al. followed 183 patients, of whom 21 (11.5%) died, for 14 days with measurements of coagulation markers at every 3–4 days.[14] At admission, they found a significant increase of D-dimer, fibrin degradation products (FDP), and prolongation of PT in nonsurvivors as compared to survivors. During the follow-up, they observed, in nonsurvivors, a further increase in D-dimer, FDP, prolongation of PT, and activated partial thromboplastin time (APTT), and a decrease in fibrinogen level and antithrombin-III activity. Finally, 15 of 21 (71.4%) deceased patients fulfilled the DIC criteria from the International Society of Thrombosis and Hemostasis (ISTH), compared to one of 162 (0.6%) lived ones.[24] However, this was not confirmed by another study, which followed 83 patients for 14 days by PT, APTT, D-dimer, fibrinogen, and platelets.[21] No decrease in fibrinogen and platelets or further prolongation of PT was observed in either survivor and non-ICU patients, or in nonsurvivors and/or ICU patients. Finally, nobody fulfilled the DIC criteria. The main difference between these two studies was that the second one routinely used prophylactic doses of low-molecular-weight heparin (LMWH).

Thus, there is clear evidence of prothrombotic coagulopathy in patients with COVID-19.


  Pathogenesis of Coronavirus Disease 2019 Coagulopathy Top


Several mechanisms were suggested to be underlying the prothrombotic changes in COVID-19. They are DIC, pulmonary intravascular coagulopathy (PIC), “microvascular COVID-19 lung vessels obstructive thrombo-inflammatory syndrome” (MicroCLOTS), secondary hemophagocytic lymphohistiocytosis (sHLH), TMA, and endotheliitis.[19],[25],[26],[27],[28] The development of DIC syndrome was detected in two studies and was not confirmed by two other reports [Table 1].[14],[21],[23],[29] Likely, DIC underlies the progressive stages of multiple organ dysfunction, which appears rapidly in the absence of prophylactic anticoagulation, and may be related to septic complications. The PIC (MicroCLOTS) phenomenon with thrombosis of pulmonary microvasculature was reported for the previous SARS infection and nonspecific ARDS.[30],[36],[37],[38] ARDS is also known as a condition with local and systemic thrombotic coagulopathy.[39],[40] Recent autopsy studies revealed thrombosis of small and mid-sized pulmonary arteries as well as microthrombi in alveolar capillaries in most of the deceased patients.[41],[42],[43],[44],[45] Thrombus in large branches of the pulmonary artery was observed in 9%–33% of dissections.[41],[43],[44] In contrast to ARDS that developed from influenza, the microcirculatory changes in novel coronavirus infection are characterized by endothelial injury with disruption of the cell membrane, nine-times more prevalent thrombosis of alveolar capillaries, and significant new vessel growth by intussusceptive angiogenesis.[38] The main difference between SARS and COVID-19 is the presence of multiple microvascular thrombi outside the lungs that were identified in capillaries of the kidney, liver, and skin.[19],[41],[43] This clinical situation may be interpreted as TMA, systemic endothelial dysfunction, or endotheliitis. It is well established that SARS-CoV-2 enters cells by endocytosis after binding to the transmembrane angiotensin-converting enzyme-2 (ACE2) protein on cells in the lung, heart, blood vessels, kidney, and gastrointestinal tract.[46] Morphological studies revealed viral RNA and intracellular viral inclusions in the kidney, brain, saphenous vein, and endothelial cells.[26],[38],[43],[44] Case series of three patients demonstrated the signs of lymphocytic endotheliitis in the kidney, intestine, lung, heart, and liver, with evidence of apoptotic bodies in the endothelium.[26] Another study identified an increased level of Willebrand factor in patients with severe infection, which favors TMA.[47] The thrombo-inflammatory response may be mediated by either endothelial injury or the activation of macrophages leading to the cytokine storm.[25] This situation may be interpreted as a specific kind of sHLH; the observed levels of ferritin favor this hypothesis.
Table 1: The incidence of thrombotic complications in patients with coronavirus disease 2019

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The specific mechanisms of prothrombotic status may be suggested as a direct endothelial injury by the virus, hypoxia, DNA, and histones of epithelial, endothelial, and neutrophil origin (neutrophil extracellular traps – NETs); inflammatory cytokines; the impaired downregulation of activated macrophages and lymphocytes; a decrease in ACE-2 in parallel with the increase in angiotensin toxicity; activation of complement; irritation of lung megakaryocytes; production of antiphospholipid antibodies; and HIT.[19],[20],[25],[27],[28],[45],[48],[49],[50],[51] There is no evidence of direct coagulation activation by the virus.[48] However, the co-localization of products linked to activation of the complement system (C4d and C5b-9) with the virus spike glycoproteins suggests the possibility of direct complement activation by SARS-CoV-2 similar to SARS-CoV.[19] It is well known that inflammation leads to increased thrombin generation, so this interaction is usually called “thromboinflammation” or “immune thrombosis.”[48] In case series of 16 patients with ARDS related to COVID-19, a significant association was demonstrated between interleukin-6 (IL-6) and fibrinogen levels.[52] At the same time, the dynamic follow-up for IL-6 and D-dimer shows the anticipatory activation of coagulation compared to the inflammatory response.[12],[50] Thus, there is no consensus on which process thrombosis or inflammation is primary in COVID-19. The population of lung megakaryocytes may be responsible for the production of activated platelets playing an essential role in thromboinflammation.[53],[54],[55] It has been shown that some viruses (H1N1 influenza, dengue, human immunodeficiency virus 1, SARS-CoV) can affect the megakaryocytes by specific receptors or through direct infection. The same mechanism was suggested in COVID-19.[45] The lupus anticoagulant was identified in 88% of ICU patients with ARDS related to COVID-19 and in 91% of infected patients with increased APTT.[23],[49] Furthermore, antiphospholipid antibodies were detected in three patients with multiple cerebral infarctions.[51] Evidence of HIT was found in 31% of ICU patients.[20] Interestingly, some individuals with HIT antibodies had no previous contact with heparin.

In general, all described mechanisms seem to be essential for the development of COVID-19-associated coagulopathy in different proportions.


  The Incidence of Venous Thromboembolism in Coronavirus Disease 2019 Patients Top


We have identified 11 studies that assessed the incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), thrombosis of other sites (ischemic stroke, acute coronary syndrome, myocardial infarction, acute limb ischemia, mesenteric ischemia, thrombosis of catheters, and extracorporeal circuits), and DIC syndrome in a total of 1735 patients, of whom 80% received VTE prophylaxis.[7],[14],[21],[23],[29],[30],[31],[32],[33],[34],[35] The epidemiological data on the prevalence of thrombotic complications in COVID-19 patients are summarized in [Table 1]. In the general ward, the prevalence of DVT ranged from 2.9% to 46.1%, with a mean value of 13% and PE from 2.8% to 30% (mean of 8%). In the ICU, DVT was found in 1.6%–27% (mean of 9%) and PE in 4.2%–50% (mean of 18%) of all patients. In most reports, the reason for VTE instrumental verification by duplex ultrasound scan (DUS) or computed tomography pulmonary angiogram (CTPA) was a clinical suspicion and/or elevation of D-dimer. However, in two studies, the total screening for DVT by DUS was performed. In the absence of pharmacological prophylaxis, DVT was found in 20 of 81 (25%) ICU patients.[7] In the general ward, DVT was detected in 66 among 143 (46.1%) patients, of whom only 37% received prophylactic LMWH.[31] Of those 66 DVTs, 23 (35%) were proximal and 43 (65%) were distal, including calf muscle veins. Patients with DVT had a worse prognosis, with more frequent admissions to the ICU, fewer discharges, and more deaths. The risk of lethal outcome was increased regardless of the localization of DVT. In another study, symptomatic and asymptomatic (random screening by DUS in 52 patients) VTE events were assessed in 198 patients, of whom 74 were admitted to the ICU.[33] The cumulative incidence of all VTE was 15% at 7 days and 34% at 14 days, with the frequency of symptomatic events of 11% and 23%, respectively. The VTE prevalence was higher in the ICU patients as compared to those in the general ward: 25% against 6.5% at 7 days, and 48% against 10% at 14 days after admission. The VTE event increased the risk of a lethal outcome by three times.

The incidence of PE was investigated in 160 patients who underwent CTPA or another type of contrast CT due to suspicion of PE or other vascular pathology.[34] Of 106 patients with confirmed novel coronavirus infection, 32 (30%) had evidence of PE compared to six of 46 (11%) patients without COVID-19. Thus, the probability of finding PE with novel coronavirus was 2.7 times higher. When CTPA was performed for clinical suspicion in 107 ICU patients, PE was found on 22 of 34 images, with a prevalence of 21%.[35] This prevalence was significantly higher in comparison to a historical cohort of all ICU patients (6.1%) and influenza patients (7.5%).

In general, the incidence of symptomatic and asymptomatic venous thromboembolism (VTE) appeared to be unexpectedly high both in the ward and in the ICU. Despite prophylaxis, it seems to be overpassing the VTE prevalence in medically and critically ill patients without prophylaxis.[56],[57],[58] Also noteworthy is the disproportion between DVT and PE that favors the hypothesis of primary thrombosis of the pulmonary artery in COVID-19.


  The Current Guidelines on the Management of Coronavirus Disease 2019 Coagulopathy Top


We have identified 11 guidelines that were published before May 22, 2020 by the ISTH; Thrombosis UK; the Italian Society on Thrombosis and Hemostasis (SISET); the Swiss Society of Hematology; multiple societies (ISTH, the North American Thrombosis Forum, the European Society of Vascular Medicine, the International Union of Angiology, and the Working Group on the Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology); the American Venous Forum (AVF); the National Institute for Public Health of the Netherlands (RIVM); the British Thoracic Society; the Anticoagulation Forum; the National Institutes of Health (NIH); and the American Society of Hematology (ASH).[8],[46],[59],[60],[61],[62],[63],[64],[65],[66],[67] The following topics for inpatients and outpatients were evaluated. For inpatients: VTE risk assessment, prophylactic anticoagulation, therapeutic anticoagulation in the absence of VTE, mechanical prophylaxis for VTE, extended prophylaxis for VTE after discharge, diagnosis and empiric treatment for VTE, management of oral anticoagulants (OACs); for outpatients: VTE risk assessment and prophylactic anticoagulation. The summary of the reviewed guidelines is represented in [Table 2].
Table 2: The content of current guidelines on the prevention and management of thrombotic complications for inpatients with coronavirus disease 2019

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VTE risk assessment for inpatients is supported by six guidelines, not mentioned by four guidelines, and not supported by only one guideline. The mentioned risk assessment models include the Padua score, Caprini score, and IMPROVE VTE score.[68],[69],[70] To the best of our knowledge, the Caprini and IMPROVE VTE scores had not been validated in COVID-19 patients as of the time of this review. The Padua score was assessed in two papers. Xu et al. evaluated the VTE and bleeding risk in 138 patients and found a high risk of VTE (Padua score of ≥4) in 17% in parallel with a high risk of bleeding (IMPROVE bleeding score of ≥7) in 7% of patients.[6] Symptomatic VTE was detected in four of 138 (2.9%) patients, among whom everyone was at a high risk of VTE (4 of 23, 17%), whereas nonmajor bleeding was detected in six patients (4.3%), among whom everyone was at a high risk of bleeding (6 of 9, 67%). Wang et al. assessed the Padua score in 1026 patients admitted to the hospital; among them, 407 (40%) had a high risk.[71] Compared to those with a low VTE risk, these patients were more often at high risk of bleeding (by the American College of Chest Physicians, 1% vs. 11%), more often admitted to the ICU (1% vs. 12%), and more often required mechanical ventilation (1% vs. 14%). However, there was no difference in mortality (0% vs. 3%), and the incidence of VTE was not reported.

Prophylactic anticoagulation for inpatients is supported by all guidelines, of which six consider pharmacoprophylaxis in accordance with the individual VTE risk, and five suggest routine use of prophylactic anticoagulation in the absence of contraindications. The interim guideline by ISTH was the first one that introduced prophylactic LMWH for all hospitalized patients with COVID-19 based on the high prevalence and unfavorable prognosis of coagulopathy. They referred to the paper by Tang et al., who found benefits of prophylactic anticoagulation in patients with significantly elevated D-dimer (>6 times the upper limit of normal [ULN]) or sepsis-induced coagulopathy (SIC).[72] The authors evaluated 28-day mortality in 449 COVID-19 patients, among whom 99 received heparins for 7 or more days (enoxaparin of 40–60 mg/day or unfractionated heparin [UFH] of 10,000–15,000 U/day). No difference was found in the overall population (30.3% vs. 29.7%). A significant decrease in mortality was observed in patients with SIC (40% vs. 64.2%) and with elevated D-dimer (32.8% vs. 52.4%). In conclusion, ISTH suggested monitoring for D-dimer, PT, platelet count, and fibrinogen level for inpatients and outpatients, with further hospital admission of those with significant abnormalities, even in the absence of clinically severe infection.

The increased (intermediate) doses of heparin are supported by five guidelines, not mentioned by two guidelines, and not endorsed by four guidelines. This approach is recommended for patients with individually increased risk of VTE (e.g., Caprini score >8, presence of multiple risk factors), obesity (e.g., body mass index [BMI] >35 kg/m2), or elevated D-dimer, and for patients admitted to the ICU. The scientific rationale, based on indirect evidence from other populations (bariatric surgery, trauma, and critical illness), suggests that intensified prophylaxis regimens may be safe and effective.[58],[73],[74],[75],[76],[77] However, there is still no scientific data on the risk/benefit ratio for this approach in COVID-19 patients. Two of four guidelines recommended against the routine use of intensified pharmacoprophylaxis and suggest this approach within clinical trials.

Therapeutic anticoagulation in the absence of VTE for inpatients is supported by four guidelines, not mentioned by only one guideline, and not endorsed by six guidelines. The general indication for the anticoagulation intensification is the high level (e.g., >2.0 mg/L or >3 times ULN) or rapid increase (>2.0–4.0 mg/L) of D-dimer and suspicion of VTE. The scientific reason for this approach is based on the hypothesis of PIC, DIC with thrombotic phenotype, the high level of fibrinogen related to heparin resistance, and the wide prevalence of pulmonary microvasculature thrombosis.[78],[79] The previous studies in patients with ARDS, including those afflicted with influenza H1N1, showed improved 7-day and 28-day survival and 33-fold reduction of VTE with empirical systemic heparin anticoagulation.[80],[81] The case series of 16 ICU patients with COVID-19 showed the ability to improve the viscoelastic properties of blood by individual adjustment of LMWH dose, transfusion of antithrombin-III concentrate, and therapy enhancing by antiplatelets.[82] Despite no evidence of VTE, seven of 16 patients ultimately died. The other cohort study assessed the effect of therapeutic anticoagulation on overall survival in 2773 patients, of whom 395 received systemic therapy with oral, subcutaneous, and intravenous anticoagulants.[83] The overall mortality did not differ in the whole sample (22.5% vs. 22.8%) but was lower in patients on mechanical ventilation, who received therapeutic anticoagulation (29.1% vs. 62.7%). Although a significant difference was obtained, the study seems to be affected by immortal time bias. The median time to initiation of anticoagulation was 2 days, with the interquartile range between 0 and 5 days. The maximal divergence of survival curves was observed within five days; after that, they became parallel. The arguments against the therapeutic anticoagulation in COVID-19 include a predominant role of pulmonary artery thrombosis that may develop by the mechanism of TMA and require different therapeutic approaches as well as the absence of evidence of improved survival with therapeutic anticoagulation in patients with sepsis and sepsis-related DIC.[84],[85] Ongoing randomized trials aim to assess the efficacy and safety of more intense intermediate-to therapeutic-dose versus prophylactic-dose LMWH in hospitalized COVID-19 patients (NCT04372589, NCT04367831, NCT04345848, and NCT04366960).

Mechanical prophylaxis of VTE for inpatient is supported by five guidelines and not mentioned by six guidelines. The common reason for its application is a contraindication to LMWH as active bleeding or a critically low level of platelets (<25–30 × 109/L). Two of five documents endorse the use of mechanical prophylaxis in addition to LMWH in ICU and immobilized patients. Only one suggests against the routine use of the combined pharmaco-mechanical approach. This suggestion appears irrational in light of the evidence of the efficacy of elastic compression stockings, intermittent pneumatic compression, and mixed pharmaco-mechanical modality in hospitalized surgical and medical patients.[86],[87],[88] The recent study showed that in patients with a Caprini score of ≥11, intermittent pneumatic compression, in addition to LMWH and anti-embolic stockings, provides a 90% reduction in postoperative symptomatic and asymptomatic venous thrombosis.[89] In the situation of the extremely high prevalence of VTE among COVID-19 patients, there seems to be no reason to ignore this evidence.

Extended prophylaxis for VTE after discharge is supported by five guidelines, not mentioned by four guidelines, and not supported by two guidelines. Four of the five documents consider individual assessment for VTE and bleeding risks before discharge, and only one suggests the routine extension of prophylactic anticoagulation for 7–14 days. LMWHs (e.g., enoxaparin of 40 mg once daily) or direct OACs (DOACs: rivaroxaban of 10 mg once daily or betrixaban of 160 mg load and then 80 mg once daily) is recommended for 28–45 days after discharge. Extended prophylaxis is generally considered for patients under the selection criteria of the specific trials.[90],[91] Particularly, it may be the IMPROVE VTE score of ≥4 or 2-3 with elevated D-dimer >two times ULN; age of >75 years or age of >60 years with D-dimer >two times ULN or the age of 40–60 years with D-dimer >two times ULN and previous VTE event or cancer. In parallel, patients should be at low risk of bleeding. The only guideline by the AVF suggests therapeutic anticoagulation after discharge in patients with D-dimer of >3 times ULN if VTE was not excluded during hospitalization. The guideline considers DUS at 2–3 weeks to make a decision regarding continuing the therapeutic regimen or switching to the prophylactic regimen. If VTE is not confirmed, the insensitivity of anticoagulation should be reduced to prophylactic for 6 weeks; if it is confirmed, full-dose anticoagulation should be continued for 3 months. The last two documents, despite a recommendation against the routine use of extended pharmacoprophylaxis, suggest this approach in carefully selected patients.

The diagnosis and empiric treatment of VTE for inpatients is represented in only six guidelines. Of those, two documents support laboratory follow-up with D-dimer and a liberal approach toward VTE verification in the absence of clinical signs. Three guidelines recommend against the use of D-dimer as a criterion for putative VTE and suggest being guided by the clinical signs. The last document demonstrates the absence of a clear position. The standard approach with pretest probability (Wells score, Geneva score) may not work correctly in patients with COVID-19 due to elevated D-dimer. Thus, diagnostic imaging, like CTPA for supposed PE and DUS for suspected DVT, is essential.[92] The clinical suspicion of PE may arise from hypoxemia or oxygen requirements disproportionate to known respiratory pathologies, hemoptysis, acute unexplained right ventricular dysfunction, unexplained tachycardia or decrease in blood pressure, acute deterioration on moving of the patient, or signs and symptoms of DVT.[46],[61],[62] If CTPA is unavailable (critically ill patient on mechanical ventilation), the right ventricular function assessed by echocardiography may be a criterion for VTE diagnosis and empiric anticoagulation.[61] However, the use of duplex ultrasound to exclude the diagnosis of PE is limited by its low sensitivity.[92] It may be reasonable in patients with a high clinical probability of PE in parallel with an increased risk of bleeding when CTPA is not possible. The positive result of DUS favors the initiation of therapeutic anticoagulation.[92]

The predictive value of D-dimer was evaluated in three trials. Zhang et al. found that D-dimer of >1.0 mg/L had a sensitivity of 88.5% and specificity of 52.9% for DVT detected by DUS.[31] At the same time, the combination of D-dimer >1.0 mg/L with a Padua score of ≥4 and a CURB-65 score (i.e., the specific scale for assessing the severity of pneumonia) of 3–5 had the same sensitivity and increased specificity of 61.4%. In another study, Cui et al. found that a D-dimer cutoff of 1.5 mg/L predicted DVT detected by DUS with a sensitivity of 85% and specificity of 89%.[7] As for PE, Leonard-Lorant et al. found that the D-dimer cutoff of >2.3 mg/L with a sensitivity of 100% and a specificity of 67% predicted the positive result of CTPA.[34] The main criticism of these studies is the small samples and the fact that the reported D-dimer cutoff in the Chinese population cannot be applied to all populations.[65] However, the use of the clinical suspicion enabled the verification of PE by CTPA in 22 of 34 (65%) ICU patients in a French hospital.[35] In the Italian hospital, the positive result of DUS and CTPA performed on clinical suspicion and/or elevated D-dimer was obtained in 46% of ward patients and 22% of ICU patients.[29]

Empiric therapeutic anticoagulation for putative VTE is supported by four guidelines and not mentioned by seven guidelines. The main reason is the inability to verify suspected VTE through appropriate imaging tests. Three of four documents suggest delayed testing when it became available, and only one document recommended continuing the full-dose anticoagulation for 3 months. The reason is the high prevalence of VTE and the economy for medical resources. Obi et al. proposed a pragmatic approach toward empiric anticoagulation in COVID-19 patients.[92] They recommended performing imaging only in patients with high VTE probability in parallel with increased bleeding risk if the results can affect the management. Otherwise, in patients with a high clinical probability of VTE and a low bleeding risk, therapeutic anticoagulation may be initiated without verification and continued 1–2 months after discharge. Further imaging for VTE is recommended after discharge to decide on the following anticoagulation.

The standard duration of anticoagulation for VTE provoked by acute medical illness is 3 months.[93] Most guidelines recommend using full-dose LMWH or UFH during inpatient treatment, followed by switching to DOACs after discharge. In the event of a high prevalence of pulmonary artery thrombosis and embolism, it is reasonable to follow patients for chronic thromboembolic pulmonary hypertension (CTEPH) for 3–6 months after the index event.[93] Currently, it is difficult to anticipate the further prevalence of CTEPH in COVID-19.

Management of OACs for inpatients is discussed by nine of 11 guidelines. Three documents recommend the switching of any OAC, either DOAC or Vitamin-K antagonist (VKA), to heparins in all patients admitted to the hospital. The other three suggested heparins only for critically ill individuals and/or those admitted to the ICU. The rationale is based on the absence of drug-drug interactions with specific therapy, better handling, and possible anti-inflammatory effects of heparins.[94] Four guidelines support the switching of VKA to DOAC for any eligible patient. However, the contraindications for DOACS (e.g., mechanical heart valves, valvular atrial fibrillation, severe renal insufficiency, breastfeeding, and antiphospholipid syndrome) and the presence of a potential drug-drug interaction should be considered. The interaction between DOACs and specific treatment for COVID-19 could be actualized on the website of the Liverpool Drug Interaction Group.[95] For example, rivaroxaban and apixaban have significant interaction with atazanavir and lopinavir/ritonavir, a nonsignificant interaction with azithromycin, chloroquine, and hydroxychloroquine, and no interaction with remdesivir. In contrast, dabigatran has significant interaction with atazanavir, lopinavir/ritonavir, chloroquine, and hydroxychloroquine, a nonsignificant interaction with azithromycin, and no interaction with remdesivir. However, DOACs are preferable to VKA because laboratory monitoring and dose adjustment are not necessary.

VTE risk assessment for outpatients is discussed by only three guidelines. Of those, two documents (SISET and multiple societies) support, and only one (NIH) recommends against, risk assessment and VTE prophylaxis. No specific risk assessment models are recommended to be utilized in outpatients. Thus, the individual risk factors (e.g., reduced mobility, BMI >30 kg/m2, previous VTE, active cancer) may be used to select eligible patients for pharmacoprophylaxis.

Prophylactic anticoagulation for outpatients is supported by two guidelines (SISET and multiple societies), not mentioned by eight guidelines, and not supported by only one (NIH) guideline. Two documents suggest the use of prophylactic anticoagulation in outpatients with increased VTE risk and a low risk of bleeding. The last document recommends against this approach. In fact, there is no evidence on the efficacy and safety of primary VTE prophylaxis with anticoagulants in outpatients.


  Conclusion Top


The prevalence of VTE in patients with COVID-19 is unexpectedly high, which requires the utilization of effective preventive protocols. The current guidelines are intermediate and highly ambiguous. They suggest prophylactic anticoagulation with LMWH or UFH in all inpatients. Intensified anticoagulation for patients without VTE is not generally recommended outside clinical trials. Elevated doses of LMWH or UFH may be considered for patients with obesity, elevated D-dimer (>2–3 times ULN), or an individually highest risk of VTE (Caprini score >8). The value of mechanical prophylaxis is underestimated by most guidelines, without objective reasons. Pharmacomechanical prophylaxis may be suggested for ICU patients and individuals at the highest risk of VTE (Caprini score >11). Extended prophylaxis after discharge may be indicated for patients with an increased risk of VTE and a low risk of bleeding. Increased D-dimer (>1.5–2.0 mg/L) may be used as an indication of VTE screening by appropriate imaging tests. If VTE is highly suspected according to the clinical signs and/or D-dimer, but the imaging test is not available, then therapeutic anticoagulation may be initiated before VTE confirmation. For putative or confirmed VTE, therapeutic anticoagulation with LMWH or UFH is preferred during inpatient treatment, followed by switching to DOACs after discharge. The duration of anticoagulation in patients with confirmed VTE should be 3 months with a focus on CTEPH in those with pulmonary artery thrombosis or embolism. The switching of VKA to DOACs and heparins should be considered for COVID-19 patients in accordance with drug-drug interaction and the severity of illness. Primary VTE prophylaxis for outpatients is not generally recommended.

Financial support and sponsorship

Nil.

Conflicts of interest

Lobastov K received honoraria for lectures, and travel grants from Bayer, Pfizer, Sanofi Aventis, Alfa Sigma, Sigvaris, researching grant from Cardinal Health; Schastlivtsev I received honoraria for lectures and travel grants from Bayer, Alfa Sigma; Porembskaya O nothing to declare; Dzhenina O received honoraria for lectures, and travel grants from Bayer, Alfa Sigma, Sigvaris, Pfizer; Bargandzhiya A nothing to declare; Tsaplin S received travel grants from Alfa Sigma.



 
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Introduction
Evidence of Coro...
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